Dual signals of TCR and Notch promote antigen-specific T cell development from pluripotent stem cells (P4370)

Abstract

Abstract The pivot in conducting a successful adoptive T-cell immunotherapy for cancer is the obtaining of a large number of naïve phenotyped, stem-cell like tumor antigen specific T cells. Previously we have reported that both conventional and antigen-specific T cells could be generated from induced pluripotent stem (iPS) cells by different methods. Here, we observed that dual signals of TCR and Notch played a significant role in antigen-specific T lineage differentiation from pluripotent stem cells. We used a murine MHC-I restricted, tyrosinase-related protein 2 (TRP2) specific TCR and Notch ligands Delta-like (DLL) 1 and 4 as a model system for inducing iPS cells to differentiate into melanoma-specific CD8+ T cells. Murine iPS cells were retrovirally transduced with TRP2-specific TCR (iPS-TRP2), and then co-cultured on OP9 bone marrow stromal cells overexpressing both DLL1 and DLL4 ligands (OP9-DL1/DL4) in the presence of Flt3L and IL-7. This approach has a better effect in terms of directing an in vitro iPS-TRP2 differentiation towards TRP2-specific CTLs. In addition, adoptive transfer of in vitro developed iPS-TRP2-derived precursor T cells into C57BL/6J mice bearing xenografted B16 melanoma significantly increased anti-tumor immunosurveillance and protected animal from tumor challenge. These data suggest that signals from TCR and Notch can cooperatively promote antigen-specific T cell development from pluripotent stem cells.